Limb amputation is associated with a devastating loss of everyday function and quality of life. Percutaneous osseointegrated implants are currently being considered to attach the exoprosthesis to the residual limb. For this methodology to succeed, an infection-free barrier must be achieved and maintained at the tissues surrounding the percutaneous pylon. The PIs propose to eliminate infections at the host-tissue/percutaneous pylon interface of osseointegrated implants by exploiting a biocompatible subdermal flange manufactured from medical grade microporous polyurethane. This flexible flange mechanically stabilizes skin to implant establishing an integral subdermal barrier, mechanically protecting the dermal barrier from inevitable impact loads, and biologically accelerating the integration of soft tissue to the percutaneous pylon, resulting in a superior subdermal barrier against both acute and chronic infections. The PIs compare two designs of soft tissue-integrating flanges on osseointegrated implants with percutaneous pylons into the tibia of a porcine model: (1) a rigid microporous titanium subcutaneous flange (baseline control), and (2) a novel flexible microporous polyurethane subcutaneous flange. Additionally, the polyurethane flange will be loaded with a clinically familiar pluripotent human protein growth factor - platelet derived growth factor beta (PDGF-BB) - for local release as a proven osteoinductive, angiogenic and dermal healing bioactive agent. In Aim 1, a subdermal barrier is created to hinder both acute and chronic percutaneous infections by promoting integration of host soft tissues with an innovative flexible microporous polymer flange attached to the pylon. This mechanically stabilizes the motion at the soft-tissue/percutaneous-pylon interface, allowing on-growth, implant-dermis sealing and infection prevention. Rates of infection, tissue attachment, vascularization, and tissue within polyurethane versus titanium flange devices will be assessed. Aim 2 seeks to demonstrate that polyurethane flanges will better protect the soft-tissue/percutaneous interface from trauma, specifically impact damage to the surrounding soft tissue. Controlled impact loads will be directed to soft- tissue/percutaneous-pylon interfaces in vivo, with the device left in situ to heal. Subsequent infection, tissue re-attachment, healing, re-vascularization, and tissue in-growth will be measured. In Aim 3, a human protein derived growth factor (PDGF-BB) currently in clinical trials will be formulated into the polymer flange for controlled release to local tissues to enhance healing responses. In vitro cell growth and migration assays will be used to maximize pharmacodynamic effects and design the protein release strategy for in vivo use. Combinations of mechanically matched polymer flanges with intrinsic tissue integration and local release of PDGF-BB from the implant will be exploited to accelerate acute phase tissue healing around the pylon, enhance the mechanical coupling to the implant interface, enhance local tissue stability against trauma, and preserve implant-associated tissue barriers to preclude infection issues. Public Health Relevance: The PIs propose to eliminate infections at the implant/tissue interface through promoting the integration and stabilization of the soft tissues to the implant pylon using a biocompatible subdermal flange manufactured from medical grade microporous polyurethane. This flexible flange mechanically stabilizes the skin to the implant establishing an integral subdermal barrier to infection, mechanically protecting the dermal barrier from inevitable impact loads, and biologically accelerating the integration of soft tissue to the percutaneous pylon, resulting in a superior subdermal barrier against both acute and chronic infections.